Cytotoxic benzodiazepine derivatives

Abstract

The invention relates to novel benzodiazepine derivatives with antiproliferative activity and more specifically to novel benzodiazepine compounds of formula (I)-(VII). The invention also provides conjugates of the benzodiazepine compounds linked to a cell-binding agent. The invention further provides compositions and methods useful for inhibiting abnormal cell growth or treating a proliferative disorder in a mammal using the compounds or conjugates of the invention.

1 . A compound represented by any one of the following formulas: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 the double line   between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H, and when it is a single bond, X is selected from —H; 
 Y is —H, —SO 3 M or —OH wherein M is —H or a cation; 
 X′ is —H; 
 Y′ is —H; 
 R x  is —(CH 2 ) p —(CR f R g )—, wherein R f  and R g  are each independently selected from —H or a linear or branched alkyl having 1 to 4 carbon atoms; and p is 0, 1, 2 or 3; 
 R e  is —H or a linear or branched alkyl having 1 to 6 carbon atoms; 
 G is —CH—; 
 Z s  is —H, —SR d , or is selected from any one of the following formulas: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 q is an integer from 1 to 5; 
 R d  is a linear or branched alkyl having 1 to 6 carbon atoms or is selected from phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl and nitropyridyl; 
 n′ is an integer from 2 to 6; 
 U is —H or —SO 3 M; and 
 M is —H or a cation. 
 
       
     
     
         2 - 3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein Z s  is —H or —SR d , wherein R d  is -Me or pyridyl. 
     
     
         5 . (canceled) 
     
     
         6 . The compound of  claim 4 , wherein Z s  is —H. 
     
     
         7 . The compound of  claim 1 , wherein R e  is —H or -Me. 
     
     
         8 . (canceled) 
     
     
         9 . The compound of  claim 1 , wherein R f  and R g  are the same or different, and are selected from —H and -Me. 
     
     
         10 - 16 . (canceled) 
     
     
         17 . The compound of  claim 1 , wherein M is —H, Na +  or K + . 
     
     
         18 - 23 . (canceled) 
     
     
         24 . The compound of  claim 1 , wherein the compound is represented by the following formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein M is —H, Na +  or K + . 
       
     
     
         25 . A conjugate comprising a cytotoxic compound and a cell-binding agent (CBA), wherein the cytotoxic compound is covalently linked to the CBA, and wherein said cytotoxic compound is represented by any one of the following formulas: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein:
 CBA is an antibody or an antibody fragment that specifically binds to a target cell; 
 the double line   between N and C represents a single bond or a double bond, provided that when it is a double bond, X is absent and Y is —H, and when it is a single bond, X is selected from —H; 
 Y is —H, —SO 3 M or —OH, wherein M is —H or a cation; 
 X′ is —H; 
 Y′ is —H; 
 R x  is —(CH 2 ) p —(CR f R g )—, wherein R f  and R g  are each independently selected from —H or a linear or branched alkyl having 1 to 4 carbon atoms; and p is 0, 1, 2 or 3; 
 R e  is —H or a linear or branched alkyl having 1 to 6 carbon atoms; 
 G is —CH—; 
 Z s1  is selected from any one of the following formulas: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein:
 q is an integer from 1 to 5; 
 R d  is a linear or branched alkyl having 1 to 6 carbon atoms or is selected from phenyl, nitrophenyl, dinitrophenyl, carboxynitrophenyl, pyridyl and nitropyridyl; 
 n is an integer from 2 to 6; 
 U is —H or —SO 3 M; and 
 M is —H +  or a cation. 
 
       
     
     
         26 . (canceled) 
     
     
         27 . The conjugate of  claim 25 , wherein Z s1  is represented by the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The conjugate of  claim 25 , wherein R e  is —H or -Me. 
     
     
         29 . (canceled) 
     
     
         30 . The conjugate of  claim 25 , wherein R f  and R g  are the same or different, and are selected from —H and -Me. 
     
     
         31 - 37 . (canceled) 
     
     
         38 . The conjugate of  claim 25 , wherein M is —H, Na +  or K + . 
     
     
         39 - 44 . (canceled) 
     
     
         45 . The conjugate of  claim 25 , wherein the conjugate is represented by any one of the following formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein M is —H, Na +  or K + . 
       
     
     
         46 - 47 . (canceled) 
     
     
         48 . The conjugate of  claim 25 , wherein the cell-binding agent is an anti-folate receptor antibody or an antibody fragment thereof, an anti-EGFR antibody or an antibody fragment thereof, an anti-CD33 antibody or an antibody fragment thereof, an anti-CD19 antibody or an antibody fragment thereof, an anti-Muc1 antibody or an antibody fragment thereof, or an anti-CD37 antibody or an antibody fragment thereof. 
     
     
         49 - 56 . (canceled) 
     
     
         57 . The conjugate of  claim 25 , wherein the antibody is huMOV19, huML66, huMy9-6, huB4, huDS6 or huCD37-3 antibody. 
     
     
         58 - 76 . (canceled) 
     
     
         77 . A pharmaceutical composition comprising the conjugate of  claim 25  and a pharmaceutically acceptable carrier. 
     
     
         78 . A method of treating a cancer in a mammal, comprising administering to said mammal a therapeutically effective amount of a conjugate of  claim 25 , and optionally, a chemotherapeutic agent. 
     
     
         79 - 80 . (canceled) 
     
     
         81 . The method of  claim 78 , wherein the cancer is ovarian cancer, pancreatic cancer, melanoma, lung cancer (e.g., non-small cell lung cancer), cervical cancer, breast cancer, squamous cell carcinoma of the head and neck, prostate cancer, endometrial cancer, lymphoma (e.g., non-Hodgkin lymphoma), myelodysplastic syndrome (MDS), peritoneal cancer, or leukemia (e.g., acute myeloid leukemia (AML), acute monocytic leukemia, promyelocytic leukemia, eosinophilic leukaemia, acute lymphoblastic leukemia (e.g., B-ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML)). 
     
     
         82 . The method of  claim 81 , wherein the cancer is acute myeloid leukemia (AML), non-small cell lung cancer or ovarian cancer. 
     
     
         83 - 84 . (canceled) 
     
     
         85 . The method of  claim 78 , wherein the conjugate is represented by 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein M is —H, Na +  or K + .